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WO2017144978A1 - Sels de (1r,2r,3s)-3-(3,4-dichlorophényl)-2-(étoxyméthyl)-8-méthyl-8-azabicyclo[3.2.1]octane et d'acétalaminoacides optiquement actifs et leur utilisation pour le traitement de troubles liés à l'obésité - Google Patents

Sels de (1r,2r,3s)-3-(3,4-dichlorophényl)-2-(étoxyméthyl)-8-méthyl-8-azabicyclo[3.2.1]octane et d'acétalaminoacides optiquement actifs et leur utilisation pour le traitement de troubles liés à l'obésité Download PDF

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Publication number
WO2017144978A1
WO2017144978A1 PCT/IB2017/000268 IB2017000268W WO2017144978A1 WO 2017144978 A1 WO2017144978 A1 WO 2017144978A1 IB 2017000268 W IB2017000268 W IB 2017000268W WO 2017144978 A1 WO2017144978 A1 WO 2017144978A1
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Prior art keywords
salt
optically active
tezofenzin
dichlorophenyl
metformin
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Russian (ru)
Inventor
Михаил Владимирович ОВЧИННИКОВ
Евгений Александрович ЧЕРТОРИЖСКИЙ
Евгений Юрьевич БЕЛОВ
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ZAMERTON HOLDINGS Ltd
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ZAMERTON HOLDINGS Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • octane and optically active acetylamino acids a method for its preparation, a product of a method, pharmaceutical compositions and a kit for treating and / or preventing disorders associated with obesity, their use and methods for treating and / or preventing disorders related to obesity.
  • the invention relates to medicine, in particular to the salt of (lR, 2R, 3S) -3- (3,4-dichlorophenyl) -2- (ethoxymethyl) -8-methyl-8-azabicyclo [3.2.1] octane (tezofenzin) and optically active acylamino acids (acetylamino acids), a method
  • the invention also relates to compositions and kits.
  • Inactivation of neurotransmitter monoamines is carried out mainly by the mechanism of reuptake into presynaptic endings. Inhibition of reuptake, there is an increase in the physiological activity of neurotransmitter monoamines.
  • tezofenzin acts by inhibiting the reuptake of serotonin, dopamine and norepinephrine in the brain structures that regulate hunger. Participants in 24-week studies of the effect of tezofenzin on weight loss achieved a weight reduction of approximately 10% (http://www.tesofensine-information.com/). However, tezofenzin in high doses causes side effects: increased
  • WO / 1997/30997 describes, in particular, a method for producing tropane derivatives, including tezofenzin, in which a compound of the formula with sodium hydride and a compound of the formula R'-SO2, where R is ethyl (ethyl sulfate) to form tropane derivatives.
  • a pharmaceutical composition comprising monoamine reuptake inhibitors, including tezofenzin, and glucose sensitizers, including metformin (WO / 2009/080691).
  • monoamine reuptake inhibitors including tezofenzin
  • glucose sensitizers including metformin
  • metformin is about 0, 1 -2 mg and 0.1 -500 mg, respectively.
  • Metformin is an oral hypoglycemic drug from the biguanide group. Metformin reduces hyperglycemia without leading to the development of hypoglycemia. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion and does not have a hypoglycemic effect in healthy individuals; increases the sensitivity of peripheral receptors to insulin and glucose utilization by cells, reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis, and delays the absorption of glucose in the intestine. Metformin stimulates glycogen synthesis by acting on glycogen synthetase.
  • metformin as a supplement to the diet in individuals with obesity and type 2 diabetes [Teupe B., Bergis K. Prospective randomized two years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Diabete Metabolisme, 1991, v. 17, p.p. 213-17] allowed metformin to be considered the first choice drug for the hypoglycemic therapy of patients with overweight and obesity.
  • antihyperglycemic agents have varying severity and
  • derivatives of sulfonylureas of the first generation have greater activity (50-100 times higher than the activity of sulfonylurea preparations
  • DPP-IV dipeptidyl peptidase IV
  • GLP-1 glucagon-like peptide-1
  • HLP-1 inhibition may be a promising approach to treating conditions such as non-insulin-dependent diabetes mellitus.
  • Dipeptidyl peptidase IV - 4 is a membrane-bound non-classical serine aminopeptidase that is localized in a number of tissues (intestines, liver, lungs, kidneys), as well as on blood T-lymphocytes (where the enzyme is known as CD-26). She is responsible for metabolic breakdown
  • GLP-1 (7-36), glucagon endogenous peptides (GLP-1 (7-36), glucagon) in vivo and exhibits
  • DPP-4 IV increases the levels of endogenous GLP-1 (7-36) and reduces the formation of its GLP-1 antagonist (9-36) and, thus, reduces the symptoms of diabetes.
  • DPP-IV inhibitors used as DPP-IV inhibitors for the treatment of conditions mediated by DPP-IV, such as non-insulin-dependent diabetes mellitus and obesity (WO 98/19998, RU2251544), which include vildagliptin, which is (S) -l- [N- (3-hydroxy-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile, as well as condensed-based dipeptidyl peptidase IV inhibitors
  • cyclopropylpyrrolidines proposed for use in the treatment of diabetes, in particular type II diabetes, as well as hyperglycemia, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases (RF 2286986), which include saxagliptin, which is (8) -3-hydroxyadamantyl glycine- B-cis-4,5-methanoprolinonitrile.
  • vildagliptin and its pharmaceutically acceptable salts in particular acid addition salts, including acetate, adipate, alginate, 4-aminocalicylate, aspartate, benzoate, carbonate, cinnamate and others, are described in WO 2007/019255.
  • beta-aminotetrahydroimidazo- (1,2-A) -pyrazines and tetrahydrotriazolo- (4, 3-A) pyrazines as inhibitors of DPP-IV for the treatment and prevention of diabetes (patent EA 006845), in particular sitagliptin, which is () -4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1, 2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] - 1 - (2,4 5-trifluorophenyl) butane-2- amine.
  • Alogliptin which is 2 - ( ⁇ 6 - [(GL) -3-aminopiperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) -yl ⁇ methyl) benzonitrile and its use for the treatment of conditions mediated by DPP-IV, are described in patents EA 013427 and EA015735.
  • Patent EA 013684 describes heterocyclic compounds of boronic acid, including dutogliptin, which is 1- [N- [3 (R) - pyrrolidinyl] glycyl] pyrrolidin-2 () -ylboric acid
  • EAO Patent 12591 describes hemigliptin, which is (3S) -3-amino-4- (5,5-difluoro-2-oxopiperidine) -1- [2,4-di (trifluoromethyl) -5,6,7,8 - tetrahydropyrido [3,4- (1] pyrimidin-7-yl] butan-1-one,
  • DPP-IV-dependent diseases for example type II diabetes mellitus.
  • Melogliptin related to pyrrolidone derivatives and representing (2S, 4S) -l- ⁇ 2 - [(3S, 1 R) -3- (l / - / - 1, 2, 4-triazol-1-ylmethyl) cyclopentylamino] acetyl ⁇ -4-fluoropyrrolidine-2-carbonitrile is described in WO / 2006/040625.
  • DP-IV inhibitors or glyptins can be used in combination with one or more antidiabetic agents other than a DPP-IV inhibitor, anti-obesity agent and / or lipid modulating agent (EA201101187, EA201101191, WO2012056372, WO2011 1 14271, WO2013062902, WO2012173877, WO2009091663).
  • a pharmaceutical combination for inhibiting the enzymatic activity of DPP-IV may include a heterocyclic boronic acid compound and an antidiabetic or antihyperglycemic agent, wherein the weight ratio of the compound to antidiabetic or
  • the antihyperglycemic agent is preferably from about 0.01: 1 to about 100: 1 (patent EA 013684). If the antidiabetic agent is biguanide, the compounds are used in a weight ratio to the biguanide in the range of from about 0.01: 1 to about 100: 1,
  • condensed cyclopropylpyrrolidines an antidiabetic agent other than a DPP-IV inhibitor and an anti-obesity agent and / or lipid modulating agent the antidiabetic agent may be an oral antihyperglycemic agent, preferably biguanide such as metformin.
  • DPP-IV inhibitors are used in a weight ratio to biguanide (metformin), about 0.01: 1-100: 1, preferably about 0.1: 1-5: 1.
  • Metformin or its salt are used in amounts of about 500-2000 mg per day, which can be administered in a single dose or in divided doses one to four times a day.
  • Antidiabetic drugs containing a DPP-4 inhibitor in particular, linagliptin
  • a DPP-4 inhibitor in particular, linagliptin
  • antidiabetic agents that can be used to treat or prevent one or more conditions selected from the group including including type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia are described in application EA 201101187.
  • glycosylated hemoglobin by any of the classes of hypoglycemic
  • the invention relates to the salt of (1K, 2K, 38) -3- (3,4-dichlorophenyl) -2- (ethoxymethyl) -8-methyl-8-azabicyclo [3.2.1] octane (tesophenzine) and optically active acylamino acids applicable to the treatment of conditions associated with overweight and obesity, and to a method for producing a salt of tezofenzin and optically active acylamino acids of the formula 4
  • R H, CH3, CH (CH3) 2, CH2CH (CH3) 2, CH2COOH, CH2CH2COOH, CH2Ph, CH2 (4-OH-Ph), CH2 (4-Cl-Ph), CH2 (4 -F-Ph), CH20H, CH (OH) CH3.
  • the proposed method for producing a salt of tezofenzin and optically active acylamino acids involves the interaction of (1K, 2K, 38) -2-hydroxymethyl-3- (3,4-dichlorophenyl) -tropane of the formula
  • R H, CH3, CH (CH3) 2, CH2CH (CH3) 2, CH2COOH, CH2CH2COOH, CH2Ph, CH2 (4-OH-Ph), CH2 (4-Cl-Ph), CH2 (4-F-Ph ), CH20H, CH (OH) CH3 to give a compound of formula 4
  • Reagents that change the hydroxyl group to halogen are selected from the group consisting of thionyl chloride SOC12, phosphorus pentachloride PC15, phosphorus trichloride PC13, hydrogen halides HC1, HBr, HI, SOBr2, PI3, RvgZ, ROS13, ROVgZ.
  • a suitable organic solvent is preferably absolute ethyl alcohol.
  • Optically active acyl amino acids are selected from the group
  • acetylglycine including acetylglycine, acetylalanine, acetylvaline, acetylleucine, acetylaspartic acid, acetylglutamic acid,
  • acetylphenylalanine acetyl tyrosine, acetyl-4-chloro-phenylalanine, acetyl-4-fluoro-phenylalanine, acetylserine, acetylthreonine.
  • reagent preferably a 2-10-fold excess of reagent, at a temperature in the range of 0-150 ° C, preferably 50-100 ° C, in an organic solvent, preferably toluene, or in the absence thereof, followed by
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active component, a tezofenzin salt with optically active acylamino acids in an effective amount and a pharmaceutically acceptable excipient.
  • Another aspect of the invention relates to a pharmaceutical composition containing, as active components, a tezofenzin salt with optically active acylamino acids in combination with an antihyperglycemic agent selected from the group consisting of DPP-IV inhibitors (glyptins), biguanides, preferably metformin, or second generation sulfonylureas, preferably glibenclamide or gliclazide, in an effective amount and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or
  • obesity including type II diabetes mellitus, contains salt
  • tesofenzin with optically active acylamino acids in an amount of from 0.1 mg to 2 mg; the rest is a pharmaceutically acceptable carrier (s).
  • the pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or obesity, including type II diabetes mellitus comprising, as active components, a tesofenzin salt with optically active acylamino acids and metformin, contains a tesofenzin salt with optically active acylamino acids in an amount of from 0.1 mg to 2 mg;
  • a pharmaceutical composition for the treatment and / or prevention of disorders associated with overweight and / or obesity comprising as active components a salt
  • dipeptidyl peptidase IV contains a tezofenzin salt with optically active acylamino acids in an amount of 0.1 mg to 2 mg and an inhibitor
  • dipeptidyl peptidase IV or a pharmaceutically acceptable salt thereof from 0.1 mg to 1000 mg; and a pharmaceutically acceptable carrier (s).
  • compositions proposed in accordance with the present invention are an effective tool for weight loss and are useful in the treatment of disorders associated with overweight or obesity, including diabetes mellitus type P.
  • Another aspect of the invention relates to a kit containing
  • a salt of tezofenzin with optically active acylamino acids and an antihyperglycemic agent selected from the group comprising a DPP-IV inhibitor (gliptin) or its salt, biguanides, preferably metformin or its salt, or second-generation sulfonylureas, preferably glibenclamide or glyclazide in oral form, and
  • Another object of the invention is the use of
  • Another object of the invention is a method for the prevention and treatment of disorders associated with overweight or obesity, including diabetes mellitus, comprising administering to a patient a pharmaceutical composition or kit according to the invention in a therapeutically effective amount.
  • R H, CH3, CH (CH3) 2, CH2CH (CH3) 2, CH2COOH, CH2CH2COOH or CH2Ph, CH2 (4-OH-Ph), CH2 (4-Cl-Ph), CH2 (4-F-Ph ), CH20H, CH (OH) CH3 to give a compound of formula 4
  • Ci Reagents that change the hydroxyl group to halogen are selected from the group consisting of thionyl chloride SOC12, phosphorus pentachloride PC15, phosphorus trichloride PC13, hydrogen halides HC1, HBr, HI, SOBr2, PI3, RvgZ, ROS13, ROVgZ.
  • the reaction of (lR, 2R, 3S) -2-hydroxymethyl-3- (3,4-dichlorophenyl) -tropane with the reagent is carried out at 1.5-100 times, preferably 2-10 times, excess of the reagent changing the hydroxyl group to halogen selected from the group including thionyl chloride SOC12, phosphorus pentachloride PC15, phosphorus trichloride PC13, hydrogen halides HC1, HBr, HI,
  • a suitable organic solvent preferably absolute ethyl alcohol.
  • the product of the proposed method is a salt of the compound (1K, 2K, 38) -3- (3,4-dichlorophenyl) -2- (ethoxymethyl) -8-methyl-8-azabicyclo [3.2.1] octane and optically active acylamino acids of formula 4 .
  • composition in accordance with the present invention containing as active components a salt of tezofenzin and optically active acylamino acids in combination with an antihyperglycemic agent selected from the group comprising DPP-IV inhibitors (glyptins) or biguanides, preferably metformin, has a more pronounced effect, which manifests itself in increasing the impact combined use in the composition of metformin, or gliptin, and a tezofenzin salt with optically active acylamino acids for overweight and / or obesity, in particular for type II diabetes mellitus.
  • an antihyperglycemic agent selected from the group comprising DPP-IV inhibitors (glyptins) or biguanides, preferably metformin
  • acylamino acids can enhance their therapeutic effect and, thus, provide preventive protection and optimize the treatment of patients with overweight and / or obesity, including type II diabetes mellitus (Examples 4-6).
  • compositions in accordance with the invention include N- (substituted glycyl) -2-cyanpyrrolidines used to treat
  • non-insulin-dependent diabetes mellitus and obesity WO 98/19998, RU2251544
  • vildagliptin which is (5) -1- [L ⁇ - (3-hydroxy-1-adamantyl) glycyl] pyrrolidine-2-carbonitrile
  • dipeptidyl peptidase IV inhibitors based on condensed cyclopropyl pyrrolidines, which are proposed for use in the treatment of diabetes, in particular type II diabetes, as well as hyperglycemia, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases (RF 2286986), which include saxagliptin, which is (8) -3-hydroxyadamantylglycine-b-cis-4,5-methanoprolinonitrile; beta-aminotetrahydroimidazo- (1,2-A) pyrazines and tetrahydrotriazolo- (4, 3-A) pyrazines
  • melogliptin related to pyrrolidone derivatives and representing (2S, 4S) -l- ⁇ 2 - [(3S, 1 R) -3- (l ⁇ - ⁇ , 2, 4-triazol-1-ylmethyl) cyclopentylamino] acetyl ⁇ -4-fluoropyrrolidine-2-carbonitrile
  • vildagliptin in particular, citrate and tartrate
  • pharmaceutically acceptable salts of dutogliptin are disclosed in WO / 2008/027273.
  • Methods for the preparation of vildagliptin and its pharmaceutically acceptable salts in particular acid addition salts, including acetate, adipate, alginate, 4-aminocalicylate, aspartate, benzoate, carbonate, cinnamate, etc., are described in WO 2007/019255.
  • Saxagliptin is used in the form of a hydrochloride or monobenzoate as described in publication WO / 2004 / 052850. Methods of saxagliptin are described in detail in publications WO / 2005/106011 and WO / 2005/1 15982. Saxagliptin in the form of tablets is described in publication WO / 2005/1 17841 .
  • compositions in accordance with the present invention can be made in the form of tablets, capsules using pharmaceutically
  • composition may be in the form of drops or solution for administration inside, or in the form of a nasal spray or nasal drops, an aerosol
  • sublingual or oral or in the form of a powder, or in the form of a lyophilisate for the preparation of a ready-made solution.
  • compositions are prepared by known methods.
  • the compositions are preferably prescribed for oral administration.
  • any pharmaceutically acceptable carriers or solvents are used to prepare the pharmaceutical compositions of the invention.
  • the pharmaceutical compositions may take the form of solutions, suspensions, tablets, pills, capsules, powders. Tablets containing various excipients, for example, sodium citrate, calcium carbonate and calcium phosphate, or any other pharmaceutically acceptable excipients, may also include various disintegrants, for example, starch,
  • binders for example, polyvinylpyrrolidone, sucrose, gelatin, gum arabic and any other pharmaceutically
  • compositions of the invention may also be soft or hard filled gelatin capsules; preferred capsules in this case include, for example, lactose or milk sugar, as well as high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, the claimed compositions may be combined with various sweetening agents to improve taste and smell, tinting agents, emulsifying agents and / or suspending agents, as well as solvents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • solutions in sesame or peanut oil or in aqueous propylene glycol can be used, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the aqueous solvent is first isotonized with a sufficient amount of a salt or glucose solution.
  • Another aspect of the invention relates to a kit containing
  • a salt of tezofenzin with optically active acylamino acids in an amount of from 0.1 mg to 2 mg, and
  • metmorphine or its pharmaceutically acceptable salt - from 400 mg to 3000 mg;
  • glibenclamide or glyclazide in an amount of 2.5 to 25 mg.
  • the invention also relates to the use of the above.
  • compositions and kit for the treatment and / or prevention of disorders are provided.
  • a change in the component composition of the body including .
  • type II diabetes mellitus including obesity with a body mass index of 27 kg / m 2 or more, with ineffective diet therapy and physical activity.
  • the proposed methods for the prevention or treatment of disorders associated with overweight and / or obesity, including type II diabetes mellitus include the introduction of pharmaceutical compositions or a kit according to the invention containing a tezofenzin salt with optically active
  • acylamino acids or a salt of tezofenzin with optically active
  • acylamino acids in combination with an antihyperglycemic agent, in a therapeutically effective amount.
  • an antihyperglycemic agent in a therapeutically effective amount.
  • single dose of salt for example, single dose of salt
  • tesofenzin with optically active acylamino acids as an active ingredient in the pharmaceutical composition may be from 0.1 mg to 2 mg.
  • the daily dose depends on the severity of the disease, the weight of the patient and the desired effect. The dose is set individually, depending on tolerability and clinical efficacy. In a most preferred embodiment, the daily dose of a tezofenzin salt with optically active acylamino acids and
  • metformin or its pharmaceutically acceptable salt as active components in the pharmaceutical composition is for
  • metformin from 400 to 3000 mg and 0.1-2 mg for a tezofenzin salt with optically active acylamino acids.
  • Metformin or its salt used in amounts of about 400-3000 mg per day, can be administered in a single dose or in divided doses one to four times a day.
  • the adult gliptin dose is preferably about 0.1-1000 mg per day, this amount can be administered as a single dose or in divided doses 1-4 times a day.
  • the daily dose for sitagliptin in the pharmaceutical composition according to the invention is from 10 mg to 200 mg, for vildagliptin - from 10 mg to 150 mg, for melogliptin - from 5 mg to 250 mg, linagliptin - from 0.5 mg to 10 mg, for saxagliptin - from 2.5 mg to 100 mg, alogliptin - from 5 mg to 250 mg, a preferred dose of dutogliptin is from 50 mg to 400 mg.
  • the daily dose of glibenclamide or gliclazide is also selected
  • composition according to the invention is individually, depending on the age, severity of diabetes, the level of hyperglycemia, and is in the composition according to the invention from 1, 25 to 20 mg (initial dose is from 2.5 to 5 mg / day, the maximum daily dose is from 20 mg to 25 mg )
  • acylamino acids and metformin for weight loss with enhanced nutrition, was studied in a group of 1653 patients, women and men aged 35-65, showing signs of obesity with a body mass index of more than 27 kg / m2 and signs of type II diabetes (Example 4).
  • the pharmaceutical composition according to the invention for weight loss has been studied in a series of clinical trials with a total number of patients 2,300, including women and men aged 40-60 years, showing signs of obesity with a body mass index of 29.7 kg / m2 - 42.6 kg / m2, and 10.5% of them had signs of type II diabetes (Example 5).
  • acylamino acids relative to monotherapy using tezofenzin or a dipeptidyl peptidase IV inhibitor (Table 2).
  • Example 1 Obtaining a salt of tezofenzin and acetyl aspartic acid.
  • the mixture is stirred for 30 minutes at the same temperature (0 C) and then heated to boiling and boiled until the reaction is complete (6-10 hours).
  • reaction mixture was again cooled to room temperature, evaporated by%, and 500 ml was added dropwise with stirring to the residue.
  • Example 4 The effect of a composition containing a salt of tezofenzin and optically active acylamino acids, and a composition containing a salt of tezofenzin with optically active acylamino acids and metformin, on weight loss.
  • Body mass index is defined as the weight of a person (in kilograms) divided by his height (in meters), squared. BMI equal to or greater than
  • BMI 28 to 35 indicates obesity of mild or moderate severity
  • BMI of 35 to 40 corresponds to severe obesity. Waist circumference exceeding 102 cm in men and
  • acylamino acids and combination therapy with metformin for changes in body weight were studied with enhanced nutrition: men received 3600-4000 kcal per day, women - 2800-3200 kcal per day. Patients received
  • compositions in the form of a set of capsules or tablets.
  • tezofenzin and optically active acylamino acids or a salt of tezofenzin and optically active acylamino acids and metformin, to reduce body weight (M ⁇ t) *.
  • Metformin hydrochloride (850) 2.25 ⁇ 0.22
  • n 100 Salt of tezofenzin and 6.1 ⁇ 0.23 acetylglutamic acid (0.25)
  • Metformin (850) p 60 Salt of tezofenzin and acetylglutamic acid 15.9 ⁇ 0.32
  • acetyl glutamic acid 0.5 mg of the salt of tezofenzin and acetylglycine; 1 mg of tezofenzin salt with acetyl aspartic acid and 2 mg of tezofenzin and acetylglycine salt decreased after 24 weeks by 4.9%; 6.1%; 1 1.2%; 13.8% and 15.7%, respectively.
  • acetylaspartic acid and 2000 mg of metformin decreased after 24 weeks by 12.3%. Weight of participants in the 0.5 mg salt group
  • tesofenzin and acetylglutamic acid and 2000 mg of metformin decreased after 24 weeks by 15.9%.
  • Those who took a composition containing 1 mg of the salt of tezofenzin and acetylglycine and 2000 mg of metformin lost about 18.1%.
  • acetylaspartic acid and 3000 mg of metformin decreased after 24 weeks by 18.1%. Weight of participants in the 0.5 mg salt group
  • composition according to the invention containing a tezofenzin salt with optically active acylamino acids up to 1.0 mg there was no increase in systolic and diastolic blood pressure and heart rate.
  • a dose of tezofenzin salt with optically active acylamino acids of 2 mg approximately 1.5% of patients had increased diastolic pressure; approximately 3.85% of participants showed an increase in heart rate.
  • composition according to the invention containing a salt of tezofenzin and optically active acylamino acids in an amount of 0.1-2 mg and metformin in an amount of 500- 3000 mg, preferably 0.25-1.0 mg of the salt of tezofenzin and optically active acylamino acids and 850-2000 mg of metformin.
  • acylamino acids and gliptin (vildagliptin or saxagliptin), or glibenclamide in the pharmaceutical composition according to the invention for weight loss
  • vildagliptin or saxagliptin with the combined use of the tezofenzin salt with the optically active acylamino acids in the pharmaceutical composition according to the invention on weight loss has been studied in a series of clinical studies, the total number of patients is 2000 women and men aged 35-52 showing signs of obesity with an index body weight more than 29 kg / m2, of which 14% had signs of type II diabetes.
  • Body mass index is defined as the weight of a person (in kilograms) divided by his height (in meters) squared.
  • a BMI equal to or greater than 28 corresponds to obesity, and a BMI from 28 to 35 indicates mild or moderate obesity, and a BMI from 35 to 40 corresponds to severe obesity.
  • a significant decrease in body weight is observed in patients taking a composition containing saxagliptin
  • Glibenclamide does not affect body weight. There were no differences in weight loss between the participants in the group who took glibenclamide in a daily dose of 2.5 mg and the salt of tezofenzin and optically active acylamino acids in a daily dose of 0.5 mg or
  • acylamino acids to regulate blood glucose.
  • vildagliptin - 50 mg or saxagliptin - 10 mg, in combination with a daily dose of 0.5 mg of tezofenzin and optically active acylamino acids, for the regulation of blood glucose was studied in patients with newly diagnosed type II diabetes mellitus who had not previously received treatment.
  • composition according to the invention containing a salt of tezofenzin and optically active acylamino acids and DPP-IV inhibitors.
  • Example 7 Preparation of compositions containing, as active components, a salt of tezofenzin and optically active acylamino acids, or a salt of tezofenzin and optically active acylamino acids in combination with an antihyperglycemic agent selected from the group consisting of DPP-IV inhibitors (glyptins), biguanides, preferably metformin, or generation II sulfonylureas, preferably
  • the granulate is obtained by pre-mixing an active pharmaceutical substance containing a salt of tezofenzin and optically active acylamino acids or a salt of tezofenzin and optically active acylamino acids in combination with an antihyperglycemic agent selected from the group comprising DPP-IV inhibitors (glyptins), biguanides, preferably metformin, or drugs
  • sulfonylureas preferably glibenclamide or glyclazide
  • excipients in a mixer with an aqueous solution of povidone and granulation, followed by drying of the granulate and calibration, and encapsulation or tabletting.
  • Excipients magnesium stearate, croscarmellose sodium and microcrystalline cellulose (MCC).
  • mannitol, magnesium stearate, and corn starch are used as adjuvants.
  • the active substance is mixed with mannitol and corn starch with an aqueous solution of povidone.
  • Magnesium stearate is added to the dried granular material. From the resulting mixture, tablets are compressed.
  • the kit includes tablets or capsules, which may, in one embodiment, contain separately 2.5 mg, 0.5 mg, 1.0 mg or 2.0 mg of a salt of optically active acetylamino acids and tezofenzin; 500 mg, 850 mg, 1000 mg or 2000 mg of metformin; from 2.5 mg to 500 mg of a DPP-IV inhibitor, in particular 50 mg or 100 mg of vildagliptin or 2.5 mg, 5 mg, 50 mg or 100 mg of saxagliptin.
  • Tablets and / or capsules are packaged in blister packs of polyvinyl chloride film and aluminum foil.
  • varnished or in a polymer container for medicines, or in polymer cans for medicines, along with instructions for use.
  • the recommended starting daily dose of a composition according to the invention may be 1 tablet or capsule containing 500 mg or 850 mg of metformin; 0.25 mg or 0.5 mg of tezofenzin salt and optically active acetylamino acids.
  • Tablets or capsules should be taken in the morning without chewing and drinking. a sufficient amount of liquid (1 glass of water) in combination with a meal.
  • the dose can be increased to 2 tablets - 1 tablet in the morning and 1 tablet in the evening.
  • the duration of treatment is from 6 to 12 months. After a 1- or 2-month break, treatment can be continued.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un sel de tesofensine comprenant des acéatlyaminoacides optiquement actifs et un procédé de production de celui-ci. L'invention concerne également des compositions pharmaceutiques comprenant un sel de tesofensine comprenant des acétylaminoacides optiquement actifs ou contenant en qualité de composants actifs un sel de (1R,2R,3S)-3-(3,4-dichlorophényl)-2-(étoxyméthyl)-8-méthyl-8-azabicyclo[3.2.1]octane avec des acétylaminoacides optiquement actifs en combinaison avec un agent anti-hyperglycémique choisi dans le groupe comprenant des inhibiteurs de DPP-IV (glyptines), biguanides, de préférence metformine ou des préparations de sulfonylurée de seconde génération, de préférence du glibenclamide ou du gliclazide; l'invention concerne également leur utilisation pour le traitement et/ou la prévention de troubles liés à un poids excédentaire et/ou l'obésité, y compris en cas de diabète sucré, ainsi que des procédés de prévention ou de traitement de troubles liés à un poids excédentaire et/ou l'obésité, y compris en cas de diabète sucré.
PCT/IB2017/000268 2016-02-25 2017-02-21 Sels de (1r,2r,3s)-3-(3,4-dichlorophényl)-2-(étoxyméthyl)-8-méthyl-8-azabicyclo[3.2.1]octane et d'acétalaminoacides optiquement actifs et leur utilisation pour le traitement de troubles liés à l'obésité Ceased WO2017144978A1 (fr)

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EA201600140 2016-02-25
EA201600140A EA028995B1 (ru) 2016-02-25 2016-02-25 Соль тезофензина и оптически активных ацетиламинокислот, их применение для лечения и/или профилактики нарушений, связанных с ожирением

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572289A (zh) * 2022-10-24 2023-01-06 龙曦宁（上海）医药科技有限公司 一种特索芬辛的合成方法

Citations (1)

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WO1997030997A1 (fr) * 1996-02-22 1997-08-28 Neurosearch A/S Derives du tropane, leur preparation et utilisation

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WO2002102801A1 (fr) * 2001-05-23 2002-12-27 Neurosearch A/S Derives du tropane et utilisation de ces derniers comme inhibiteurs de recaptage du neurotransmetteur monoamine

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WO1997030997A1 (fr) * 1996-02-22 1997-08-28 Neurosearch A/S Derives du tropane, leur preparation et utilisation

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Title
KUMAR ET AL: "An overview of automated systems relevant in pharmaceutical salt screening", DRUG DISCOVERY TODAY, ELSEVIER, AMSTERDAM, NL, vol. 12, no. 23-24, 29 November 2007 (2007-11-29), pages 1046 - 1053, XP022370272, ISSN: 1359-6446, DOI: 10.1016/J.DRUDIS.2007.08.002 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115572289A (zh) * 2022-10-24 2023-01-06 龙曦宁（上海）医药科技有限公司 一种特索芬辛的合成方法

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